A5058793243- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Glioma Diagnosis and Treatment
- Immune cells in cancer
- RNA Interference and Gene Delivery
- Immune Cell Function and Interaction
- Virus-based gene therapy research
- interferon and immune responses
- Cancer Research and Treatments
- Chemokine receptors and signaling
- T-cell and B-cell Immunology
- Cancer, Stress, Anesthesia, and Immune Response
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA Research and Splicing
- Inflammatory mediators and NSAID effects
- vaccines and immunoinformatics approaches
- Nanoplatforms for cancer theranostics
- Brain Metastases and Treatment
- RNA modifications and cancer
- Nanowire Synthesis and Applications
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Single-cell and spatial transcriptomics
- Eicosanoids and Hypertension Pharmacology
Neurological Surgery
2016-2025
University of California, San Francisco
2016-2025
Parker Institute for Cancer Immunotherapy
2017-2025
UCSF Helen Diller Family Comprehensive Cancer Center
2015-2025
City College of San Francisco
2017-2025
UPMC Hillman Cancer Center
2010-2023
University of Pittsburgh
2010-2023
University of Pittsburgh Medical Center
1999-2021
Northwestern University
2016-2021
University of California, San Diego
2021
A trial of autologous T cells redirected to a specific mutation in glioblastoma patients illustrates mechanisms resistance.
Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs a barrier to emerging immunotherapies. It is unknown what extent derived from peripheral blood adopt the phenotype of brain-resident microglia pre-treatment gliomas. The relative proportions blood-derived have been poorly quantified clinical samples due paucity markers that distinguish these cell types malignant tissue. We perform single-cell RNA-sequencing human identify phenotypic differences distinct...
A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded synthetic peptides for glioma-associated antigen (GAA) epitopes administration polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients recurrent malignant gliomas. GAAs these are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, gp100.Twenty-two (13 glioblastoma multiforme [GBM],...
A chimeric antigen receptor redirects T cells to treat glioblastoma.
Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production prostaglandin E₂ (PGE₂). Because PGE₂ induces expansion myeloid-derived suppressor cells (MDSC), we hypothesized blockade would suppress gliomagenesis by inhibiting MDSC development accumulation tumor microenvironment (TME). In mouse models glioma, treatment with...
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among first genetic alterations observed during development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced cytotoxic T lymphocyte-associated IFN-γ-inducible chemokines, including CXCL10, IDH-mutated (IDH-MUT) tumors...
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show multi-antigen prime-and-kill recognition circuits provide flexibility precision to overcome these challenges in context glioblastoma. A synNotch recognizes a priming antigen, such as heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor splice variant III (EGFRvIII) or...
Abstract Although type I IFNs play critical roles in antiviral and antitumor activity, it remains to be elucidated how are produced sterile conditions of the tumor microenvironment directly affect tumor-infiltrating immune cells. Mouse de novo gliomas show increased expression IFN messages, mice, CD11b+ brain-infiltrating leukocytes (BIL) main source that induced partially a STING (stimulator genes)-dependent manner. Consequently, glioma-bearing StingGt/Gt mice showed shorter survival lower...
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. majority of midline gliomas, including more 70% DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 histone 3 variant (H3.3). From a CD8+ T cell clone established by stimulation HLA-A2+ cells synthetic peptide encompassing the H3.3K27M mutation, complementary DNA receptor (TCR) α- and β-chains were cloned into retroviral vector. TCR-transduced...
Diffuse brainstem gliomas (BSGs) and other high-grade (HGGs) of childhood carry a dismal prognosis despite current treatments, new therapies are needed. Having identified series glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated pilot study subcutaneous vaccinations with GAA epitope peptides HLA-A2-positive children newly diagnosed BSG HGG.GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), survivin, their peptide epitopes emulsified...
<h3>Background</h3> Systemic and local immune suppression plays a significant role in glioma progression. Glioma microenvironment contains both brain-resident microglial cells (MG) bone marrow-derived macrophages (BMDM), but the study of their functional regulatory activity has been hampered until now by lack markers allowing proper identification isolation to collect pure populations. <h3>Methods</h3> Myeloid lymphoid infiltrate were characterized grade II, III IV gliomas multicolor flow...
The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations enhance therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions identify genes that targeted prevent dysfunction. These converged on RASA2, a RAS GTPase-activating protein...
Abstract Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, emerging evidence suggests that these extend to genetic/epigenetic cellular differences, including immune responses. However, the mechanisms driving immunologic sex not fully understood. Here, we demonstrate T cells play a critical role GBM differences. Male mice exhibited accelerated tumor growth, with decreased frequency increased exhaustion of CD8+ tumor. Furthermore, higher progenitor exhausted was...
Abstract T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens 1 . However, their efficacy is limited tumours with few somatic mutations and substantial intratumoural heterogeneity 2–4 Here we introduce a previously uncharacterized class tumour-wide public neoantigens originating from RNA splicing aberrations diverse types. We identified cell receptor clones capable recognizing targeting derived aberrant GNAS...
Abstract Background Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve efficacy vaccine strategies directed against CNS tumors, we evaluated whether administration a ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine carboxymethylcellulose (poly-ICLC) would enhance anti-CNS tumor effectiveness...
The RNase III endonuclease Dicer plays a key role in generation of microRNAs (miRs). We hypothesized that regulates cancer cell susceptibility to immune surveillance through miR processing. Indeed, disruption up-regulated intercellular adhesion molecule (ICAM)-1 and enhanced the tumor cells antigen-specific lysis by cytotoxic T-lymphocytes (CTLs), while expression other immunoregulatory proteins examined was not affected. Blockade ICAM-1 inhibited specific CTLs against Dicer-disrupted cells,...
Abstract Malignant gliomas are lethal cancers in the brain and heavily infiltrated by myeloid cells. Interleukin-4 receptor-α (IL-4Rα) mediates immunosuppressive functions of cells, polymorphisms IL-4Rα gene associated with altered glioma risk prognosis. In this study, we sought to evaluate a hypothesized causal role for suppressor cells development. both mouse de novo human glioblastoma cases, was upregulated on glioma-infiltrating but not periphery or normal brain. Mice genetically...
Abstract Purpose: Allogeneic glioma cell lines that are partially matched to the patient at class I human leukocyte antigen (HLA) loci and display tumor-associated antigens (TAA) or antigenic precursors [tumor precursor proteins (TAPP)] could be used for generating whole tumor vaccines or, alternatively, extraction of TAA peptides make autologous dendritic vaccines. Experimental Design: Twenty were characterized by molecular phenotyping flow cytometry HLA expression. Twelve 20 lines, as well...